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| First Name: | Nathaniel | | Last Name: | Milton | | Title: | Dr | | Advanced Degrees: | PhD | | Affiliation: | University of Westminster | | Department: | Department of Human and Health Sciences | | Street Address 1: | School of Life Sciences | | Street Address 2: | 115 New Cavendish Street | | City: | London | | State/Province: | England | | Zip/Postal Code: | W1W 6UW | Country/Territory: | United Kingdom | | Phone: | +44 (0) 7950 144 366 | | Fax: | +44 (0) 20 7911 5087 | | Email Address: |  |
Disclosure:
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Member reports the following financial or other potential conflicts of interest: [Last Modified: 12 September 2012]
My research has previously been funded by Insight Biotechnology Ltd and I held an honorary position of Research Director with them (Sept 1996 - March 2004).
I was the Co-founder and Research Director of NeuroDelta Ltd (May 2003 - May 2007).
I am the Founder and Director of the dormant company DeltaNeuron Ltd (Previously known as Phosphoamyloid Ltd) (April 2007 - Present)
I am the named inventor on patent applications held by Roehampton University for Kissorphin peptides use in Alzheimer's Disease, Diabetes and Creutzfeldt-Jakob Disease.
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View all comments by Nathaniel Milton
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Aging Process, Alzheimer Disease, Prion Diseases, Neurodevelopmental Disorders (Down syndrome, etc.), Stroke and Trauma, Parkinson Disease
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Apoptosis/Cell cycle, Neurotransmission, Oxidative Stress, Diagnosis, Neurobiology, Bioinformatics/Statistics, Protein structure/chemistry, Proteomics, Drug screening, Signal transduction, Stem cells, Neuroimmunology, Neuropathology, Chemistry/Pharmacology, A-beta PP/A-beta, Microscopy, Molecular and Cell biology
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I have shown that the amyloid-beta peptide specifically binds to kisspeptin. The kisspeptin peptide inhibits amyloid-beta toxicity and a hexapeptide fragment, termed kissorphin, is also able to do this. Cell lines over expressing the kisspeptin gene (KiSS-1) are resistant to amyloid peptide toxicity.
The antioxidant enzyme catalase also binds amyloid-beta with high affinity and this inhibits peroxidase enzyme activity. The mechanisms for this enzyme inhibition have been characterised in a cell free system. Monoclonal antibodies against the active component of the amyloid-beta peptide have been produced. Catalase also binds amyloid fibrils containing the 29-32 region of amyloid-beta.
The role of endogenous catalase in an in vitro cytotoxicity assay has also been characterised. Using cytotoxicity and catalase inhibition assays plus recognition sequence comparisons I have also been used to identify the binding domains of known amyloid-beta binding proteins including catalase.
I have shown that cannabinoids including noladin ether and anandamide are neuroprotective against amyloid-beta. The protective mechanism is mediated via cannabinoid CB1 receptor activation of p42/p44 MAP kinase pathways.
I have empolyed an anti-sense peptide approach to identify amyloid-beta peptide binding domains within enzymes.
Studies have focused on in vitro assays to characterise Alzheimer’s amyloid-beta peptide interactions with binding proteins.
I have shown that amyloid-beta is a substrate for the cdc2 protein kinase and have identified the amyloid-beta serine 26 residue as the target for phosphorylation. I have also characterised the regions of the enzyme and amyloid-beta required for the formation of the enzyme-substrate complex. Enzyme derived peptides that antagonise these reactions have been identified and antibodies raised against them. |
Milton, N.G.N., Chilumuri, A., Rocha-Ferreira, E., Nercessian, A.N. & Ashioti, M. (2012) Kisspeptin prevention of amyloid-ß peptide neurotoxicity in vitro. ACS Chem. Neurosci., (DOI: 10.1021/cn300045d).
Milton, N.G.N. (2012) In vitro activities of Kissorphin, a novel hexapeptide KiSS-1 derivative, in neuronal cells. J. Amino Acids, 2012, 691463.
Milton, N.G.N. & Harris, J.R. (2012) Fibril formation and toxicity of the non-amyloidogenic rat amylin peptide. Micron, (in press - PubMedID: 22854213)
Milton, N.G.N. & Harris, J.R. (2010) Human islet amyloid polypeptide fibril binding to catalase: a transmission electron microscopy and microplate study. The Scientific World JOURNAL, 10, 879–-893.
Milton, N.G.N. & Harris, J.R. (2009) Polymorphism of amyloid-beta fibrils and its effects on human erythrocyte catalase binding. Micron, 40, 800-810.
Milton, N.G.N. (2005) Phosphorylated amyloid-beta: the toxic intermediate in alzheimer's disease neurodegeneration. Subcell Biochem. 38, 381-402.
Milton, N.G.N. (2004) Role of hydrogen peroxide in the aetiology of Alzheimer's disease : implications for treatment. Drugs Aging., 21, 81-100.
Milton, N.G.N. (2002) Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Neurosci. Lett., 332, 127-30.
Milton, N.G.N. (2002) The amyloid-beta peptide binds to cyclin B1 and increases human cyclin-dependent kinase-1 activity. Neurosci. Lett., 322, 131-3.
Milton, N.G.N. (2001) Inhibition of catalase activity with 3-amino-triazole enhances the cytotoxicity of the Alzheimer’s amyloid-beta peptide. NeuroToxicology 22, 767-74.
Milton, N.G.N. (2001) Phosphorylation of amyloid-beta at the serine 26 residue by human cdc2 kinase. NeuroReport 12, 3839-44.
Milton, N.G.N., Mayor, N.P. & Rawlinson, J. (2001) Identification of amyloid-beta binding sites using an antisense peptide approach. NeuroReport, 12, 2561-6.
Milton, N.G.N. (1999) Amyloid-beta binds catalase with high affinity and inhibits hydrogen peroxide breakdown. Biochem. J., 344, 293-6. |
What is the physiological role of amylid-beta?, once we know what it should do we might be able to control its actions and role in pathological processes. |
Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, Mc Donald JM, Wüllner U, Glebov K, Heneka MT, Walsh DM, Zweckstetter M, Walter J. (2011) Extracellular phosphorylation of the amyloid β-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J. [Apr 28. - Epub ahead of print]
Habib LK, Lee MT, Yang J. (2010) Inhibitors of catalase-amyloid interactions protect cells from beta-amyloid-induced oxidative stress and toxicity. J Biol Chem. 285(50):38933-43.
Chen X, Zhang J, Chen C. (2011) Endocannabinoid 2-arachidonoylglycerol protects neurons against β-amyloid insults. Neuroscience. 178:159-68. |
Full characterisation of the roles and actions of phosphorylated amyloid-beta peptide |
The Phosphoamyloid hypothesis (Milton, N.G.N. (2005) Phosphorylated amyloid-beta: the toxic intermediate in alzheimer's disease neurodegeneration. Subcell Biochem. 38, 381-402):
Incresed amyloid-beta production and accumulation in senile plaques leads to:
(1) Increased activity of cyclin-dependent protein kinases
(2) Increased intracellular amyloid-beta.
Both (1) and (2) result in phosphorylation of amyloid-beta and the generation of a highly toxic intermediate which in turn leads to neurodegenerative changes. |
Amyloid-beta knock ins which cannot be phosphorylated - they've only tried the Ser8/Asp substitutes so far in Drosophila; still a real need for a Ser/Ala substitute at Ser26. |
Amyloid-beta phosphorylation plays a role in the clearance of Amyloid-beta |
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